Background: Accurate risk assessment for carcinogens requires an understanding of the link between the presence of the chemical in human tissues and the resulting biological effects of the exposure. Human variation in metabolism and exposure response mediates susceptibility to environmentally induced disease. New methods are being developed to measure the phenotypic effects of exposure and for studying genetic changes that may be directly in the pathway of the disease process. The goals of this project are to discover new genes in environmental response pathways and new polymorphisms in these response pathways. Hypothesis: Genes important in exposure/disease pathways may display genotypic and phenotypic variation and this variation is relevant to disease susceptibility. Aims: 1) Develop technology and model systems useful in discovery projects. 2) Identify human genes that are differentially expressed following exposure to DNA damaging agents and nongenotoxic carcinogens such as arsenic. 3) Identify environmental response genes that display differences in expression among individuals. 4). Identify functionally relevant polymorphisms in environmental response genes through sequencing and bioinformatic approaches. Accomplishments: 1) Developed a set of bioinformatic (SNPcon) tools that identify single nucleotide polymorphisms (SNPs) in transcription factor binding sites, and analyzes other features of SNP sequence characteristics in order to identify candidate functional SNPs (Tomso and Bell, manuscript in preparation). 2) Identification of sequences that are over-represented at polymorphic sites, suggesting a role for CpG dinucleotide and other sequence motifs in the generation of human polymorphism (Tomso and Bell, manuscript in preparation).3) In order to characterize dose response prior to expression array experiments to identify differentially expressed genes, we have exposed human cell lines to UV, B[a]P, BPDE, H2O2, and arsenic. Preliminary expression profiling suggests the presence of several candidate arsenic susceptibility genes (M. Miller, Y. He).4) Using gene expression profiling in lymphoblastoid cell lines, we have identified a novel and common, low expression phenotype for a prostaglandin E synthase gene and have identified a single nucleotide polymorphism in the promoter associated with this phenotype (Faulkner, Watson, and Bell, manuscript in preparation). Significance: Development of these methods and the identification and characterization of these response genes will allow us to test hypotheses concerning the role of environmental and genetic factors in the etiology of human disease.